Genome sequencing and the identification of epigenetic marks by projects such as ENCODE and the Epigenomics Roadmap Project have transformed biomedical research. Technologies for targeted manipulation of these epigenetic properties are necessary to transform the knowledge gained from these projects into tangible scientific advances and benefits for human health, such as gene therapies that modify the epigenetic code at targeted regions of the genome and the engineering of epigenome-specific drug screening platforms. To address this technology gap, we are developing a suite of well-characterized tools for custom locus- and cell type-specific modification of any epigenomic property with precise spatiotemporal control. These tools consist of fusion proteins of programmable DNA-binding proteins and enzymes that control genome structure and function. These epigenetic modifiers (EGEMs) can be specifically targeted to nearly any site in the genome. Optimized EGEM designs will be tested on both proximal and distal regulatory elements that represent diverse chromatin states, including active, repressive, bivalent, and imprinted marks. The generality of EGEMs will be shown on additional high-value targets that have broad relevance to disease. Importantly, all of these tools function independent of cell- and species-type, and therefore are useful to all fields of biologic research. Comprehensive characterization of EGEM activity in human cells will be provided by targeted and genome-wide analysis of DNA-binding, chromatin structure, and gene regulation. A validated optogenetic approach for controlling protein localization with blue light will be used to achieve precise spatiotemporal control of EGEM activity. The utility of the tool set of epigenetic modifiers will b demonstrated by impacting gene regulation in a manner that is robust, specific, and heritable. We will test the working hypothesis that different genes will require a customized set of epigenetic modification(s) to achieve efficient changes in gene expression. The specificity and stability of epigenetic modifications will be of broad utility to the fields of genomics, epigenomis, imprinting, gene therapy, developmental biology, regenerative medicine, and drug development.